5-(2-Pyrroyl)-1,2-dihydro-3H-pyrrolo 1,2-a!pyrrole-1-carboxylic acid derivatives and process for the production thereof

ABSTRACT

Novel 5-(2-pyrroyl) and 5-(N-lower alkyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo 1,2-a!pyrrole-1-carboxylic acid compounds represented by the formula: ##STR1## and the pharmaceutically acceptable, non-toxic esters and salts thereof, wherein each of R and R 1  is independently hydrogen or a lower alkyl group having from 1 to 4 carbon atoms and process for the production of such compounds; 5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo 1,2-a!pyrrole-1-carboxylic acid is representative of the class. These compounds are useful as anti-inflammatory analgesic and anti-pyretic agents and as smooth muscle relaxants.

The present invention relates to certain novel pyrrole-1-carboxylic acidcompounds and to a process for the production thereof.

More particularly, this invention relates to novel 5-(2-pyrroyl) and5-(N-lower alkyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo1,2-a!pyrrole-1-carboxylic acids represented by the formula ##STR2## andthe individual (l)-acid isomers and the (d)-acid isomers thereof and thepharmaceutically acceptable, non-toxic esters and salts thereof, whereineach of R and R¹ represents independently hydrogen or a lower alkylgroup having from 1 to 4 carbon atoms, and to the method for theproduction thereof.

The R and R¹ alkyl groups are preferably of straight chain, i.e.,methyl, ethyl, n-propyl and n-butyl.

The compounds of the present invention as described above and more fullybelow, exclusive of the (d)-acid isomer and derivatives thereof, exhibitanti-inflammatory, analgesic and anti-pyretic activities and thus areuseful in the treatment of inflammation, pain and/or pyrexia in mammals,as described hereinafter in detail. They are also smooth musclerelaxants.

The term "pharmaceutically acceptable, non-toxic esters and salts" asused herein refers to "alkyl esters" derived from hydrocarbons ofbranched or straight chain having from one to twelve carbon atoms andsalts derived from pharmaceutically acceptable non-toxic inorganic andorganic bases, respectively.

Typical alkyl ester groups are, for example, methyl, ethyl, propyl,isopropyl, butyl, t-butyl, isoamyl, pentyl, isopentyl, hexyl, octyl,nonyl, isodecyl, 6-methyldecyl and dodecyl esters.

Salts derived from inorganic bases include sodium, potassium, lithiumammonium, calcium, magnesium, ferrous, zinc, copper, manganous,aluminum, ferric, manganic salts and the like. Particularly preferredare the ammonium, potassium, sodium, calcium and magnesium salts. Saltsderived from pharmaceutically acceptable organic non-toxic bases includesalts of primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, such as isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine,2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly preferredorganic non-toxic bases are isopropylamine, diethylamine, ethanolamine,piperidine, tromethamine, dicyclohexylamine, choline and caffeine.

The novel compounds of Formulas (A) and (XI) depicted below exist aspairs of optical isomers (or enantiomorphs), i.e., a (dl) mixture, andeach optical isomer as well as the (dl) mixtures thereof are includedwithin the present invention.

When the novel compounds of this invention are to be used to elicit aphysiological response (e.g., anti-inflammatory, analgesic oranti-pyretic activity), i.e., they are to be used as medicinals, apreferred sub-grouping is that of the compounds of Formula (A) and the(l)-acid isomers thereof and the esters and pharmaceutically acceptablesalts thereof.

A still further sub-grouping, for compounds to be used as medicinals,are the compounds of Formula (A) and the (l)-acid isomer of Formula (A)and the esters and pharmaceutically acceptable salts thereof wherein Ris hydrogen and R¹ is methyl.

The (d)-acid isomer of Formula (A) and the esters and pharmaceuticallyacceptable salts thereof are useful as intermediates for the preparationof the (dl)-acid of Formula (A), as described more fully below.

The novel (dl) compounds of the present invention can be prepared by aprocess illustrated by the following reaction sequence: ##STR3## whereinR and R¹ have the above-indicated meaning and R² is a lower alkyl groupof 1 to 4 carbon atoms, e.g., methyl, ethyl, isopropyl and n-butyl.

In practicing the process outlined above, equimolecular amounts ofethanolamine (I) and dimethyl 1,3-acetonedicarboxylate (II) are reactedat a temperature of from about 0° C to about room temperature, toreadily form the vinylamine of Formula (III). To prepare the compound ofFormula (IV), wherein R is hydrogen, a solution of compound (III) in asuitable inert organic solvent, is treated under anhydrous conditions,with 2-bromoacetaldehyde or 2-chloroacetaldehyde, at from about 40° C toabout 100° C for a period of time of from about 30 minutes to about 16hours. Suitable solvents for this reaction are the aprotic solvents suchas acetonitrile, tetrahydrofuran, dimethoxyethane, chloroform,dichloromethane and the like. In the preferred embodiments, the reactionis conducted in acetonitrile solution, at reflux temperature for about 1hour. The 2-bromo-(chloro)-acetaldehyde reagents are known compounds, orcan be obtained by pyrolysis of the corresponding diethyl acetals in thepresence of oxalic acid dihydrate. To prepare the compounds of Formula(IV), wherein R is a lower alkyl group, preferably straight chain,containing 1 to 4 carbon atoms, an aqueous mixture of ethanolamine (I)and dimethyl-1,3-acetonedicarboxylate (II) is treated with a compound ofthe formula ##STR4## wherein X is bromo or chloro and R₃ is a loweralkyl group, preferably straight chain, of from 1 to 4 carbon atoms, andmost preferably 1-bromo-acetone, 1-bromo-2-butanone,1-bromo-2-pentanone, and 1-bromo-2-hexanone, at from about -20° C toabout 40° C, for a period of time from about 30 minutes to about 16hours. In the preferred embodiments the reaction is conducted at about-10° C to room temperature for about 1 to about 6 hours. The ##STR5##reagents are known compounds.

Esterification of a compound (IV) with methanesulfonyl chloride in thepresence of a tertiary amine, i.e., triethylamine, pyridine and thelike, optionally in the presence of a cosolvent such as dichloromethane,at a temperature of from about -10° C to about room temperature, forabout 10 minutes to about 2 hours produces the corresponding mesylate ofFormula (V), which is converted into the correspondingN-(2-iodoethyl)pyrrole of Formula (VI) by reaction with sodium iodide inacetonitrile solution, at reflux temperature for from about one to aboutten hours.

Upon reaction of the iodoethyl compounds of Formula (VI) with sodiumhydride in a suitable inert organic solvent such as dimethylformamidethere are obtained dimethyl 1,2-dihydro-3H-pyrrolo1,2-a!pyrrole-1,7-dicarboxylate and the 6-alkyl substituted derivativesthereof (VII). This cyclization is conducted under an inert atmosphere,i.e., under argon or nitrogen atmosphere, at temperatures of the orderof from about 15° to about 40° C, for a period of time of from about 15minutes to about 4 hours. Best results are obtained conducting thereaction at room temperature, for about 30 minutes when R is H.

Alternatively, the compounds of Formula (VII) can be prepared by directcyclization of the mesylate (V), with sodium hydride indimethylformamide solution, at from about -10° C to about roomtemperature, for from about 30 minutes to about 2 hours.

Basic hydrolysis of a compound of Formula (VII) with an alkali metalhydroxide or alkali metal carbonate, e.g., sodium hydroxide, potassiumhydroxide, sodium carbonate, potassium carbonate and the like in anaqueous lower aliphatic alcohol, e.g., methanol or ethanol, at atemperature of between room temperature and reflux, for from about 4 toabout 24 hours, affords the corresponding free diacid of Formula (VIII),i.e., 1,2-dihydro-3H-pyrrolo 1,2-a!pyrrole-1,7-dicarboxylic acid and the6-alkyl derivatives thereof. The hydrolysis is preferably carried outusing aqueous methanolic potassium hydroxide, at reflux temperature forabout 6 hours to about 10 hours.

The carboxylic acid group at the C-1 position in compound (VIII) is thenselectively esterified by treatment with a lower aliphatic alcohol,e.g., methanol, ethanol, isopropanol, n-butanol and the like, in thepresence of hydrogen chloride, to produce the corresponding alkyl1,2-dihydro-3H-pyrrolo 1,2-a!pyrrole-1-carboxylate-7-carboxylic acid ofFormula (IX). The reaction is conducted at a temperature of from about0° to about 50° C, for about 1 to about 4 hours.

Decarboxylation of the monoesterified compounds (IX) to thecorresponding compounds of Formula (X), the key intermediates in theprocess for obtaining the compounds of the present invention, isachieved by heating (IX) at an elevated temperature, of the order offrom about 230° to about 280° C for a period of time sufficient tocomplete the reaction. The course of the reaction can be followed by therate of carbon dioxide evolution and t.l.c. analysis, thedecarboxylation being generally completed within from about 45 to about90 minutes. The reaction product, namely alkyl 1,2-dihydro-3H-pyrrolo-1,2-a!pyrrole-1-carboxylate and the 6-alkyl derivatives thereof (X) canbe purified by chromatographic techniques. Alternatively, andparticularly for the decarboxylation of small batches of compound (IX),the reaction product (X) can be distilled directly from the reactionvessel.

Condensation of a compound (X) with an amide of the formula ##STR6##wherein R¹ has the above-indicated meaning, affords the correspondingalkyl 5-(2-pyrroyl)-1,2-dihydro-3H-pyrrolo- 1,2-a!pyrrole-1-carboxylate(XI). This reaction is conducted in an inert organic aprotic solvent andin the presence of phosphorous oxychloride, at reflux temperature forfrom about 15 to about 70 hours, under an inert atmosphere, followed byfurther reflux in the presence of sodium acetate, for from about 20minutes to about 1 hour. Alternatively, instead of phosphorousoxychloride other acid chlorides such as phosgene or oxalyl chloride maybe used.

In the preferred embodiments, this condensation is carried out by addinga solution of compound (X) in a suitable solvent to a previouslyrefluxed mixture of 1.1 to 2 molar equivalents of both the desired amideand phosphorous oxychloride in the same solvent, refluxing the reactionmixture thus obtained for from about 17 to about 50 hours under an argonatmosphere and thereafter adding thereto from about 3 to about 10 molarequivalents of sodium acetate, followed by an additional reflux periodfor about 30 minutes.

Adequate solvents for this reaction are the halogenated hydrocarbonssuch as dichloromethane, 1,2-dichloroethane, chloroform, carbontetrachloride and the like, dimethoxyethane and tetrahydrofuran. Thepreferred solvent is 1,2-dichloroethane.

Suitable amides are: N,N-dimethylpyrrole-2-carboxamide,N,N-dimethyl-1-methylpyrrole-2-carboxamide,N,N-dimethyl-1-ethylpyrrole-2-carboxamide,N,N-dimethyl-1-propylpyrrole-2-carboxamide andN,N-dimethyl-1-butylpyrrole-2-carboxamide.

These amides can be prepared in a conventional manner from thecorresponding pyrrole-2-carboxylic acids i.e., by conversion into theacid chlorides followed by treatment with dimethylamine. TheN-alkylpyrrole-2-carboxylic acids are known, or can be prepared from thecorresponding N-alkylpyrroles, by the methods described by A. Treibs etal., in Liebigs Ann. Chem. 721, p. 105 (1969).

Upon alkaline hydrolysis of the alkyl ester group in a compound ofFormula (XI) there is obtained the corresponding free acid of Formula(A). This hydrolysis is effected in a conventional manner, with analkali metal hydroxide or alkali metal carbonate, e.g., sodiumhydroxide, potassium hydroxide, sodium carbonate, potassium carbonateand the like, in an aqueous lower aliphatic alcohol, e.g., methanol,ethanol and the like, at a temperature of from about room temperature toreflux, for from about 15 minutes to about 2 hours, under an inertatmosphere. In the preferred embodiments, this hydrolysis is effectedwith aqueous methanolic potassium carbonate, at reflux temperature forabout 30 minutes.

The compounds of Formula (A) can be resolved, according to methods knownin the art, to obtain the corresponding individual isomers thereof.

The (l)-acid isomers and (d)-acid isomers of the compounds of Formula(A) can be obtained by conventional techniques, e.g., by applying theknown technique of high pressure liquid chromotography (HPLC) to theα-phenethyl diastereoisomeric esters of the compounds of Formula (A),followed by acid cleavage. Thus, for example, the compounds of Formula(A) wherein R is hydrogen and R¹ is methyl can be subjected to furthertreatment, according to standard methods known to the art, in accordancewith the following flow diagram: ##STR7##

The (A¹)-(l)-acid isomer and (A¹)-(d)-acid isomer referred to above are(l)-5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo1,2-a!pyrrole-1-carboxylic acid and(d)-5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo1,2-a!pyrrole-1-carboxylic acid, respectively.

The free acids of Formula (A) can be converted into other alkyl estershaving from 1 to 12 carbon atoms by conventional methods, e.g., bytreatment with (a) the alcohol corresponding to the desired ester in thepresence of a strong mineral acid, (b) an ethereal diazoalkane or (c)the desired alkyl iodide in the presence of lithium carbonate. The(l)-acid isomers can be converted into their alkyl esters by the methodsof (b) and (c) above.

The salt derivatives of the compounds of Formula (A) and the (l)-acidisomers thereof are prepared by treating these free acids with anappropriate amount of a pharmaceutically acceptable base. Representativepharmaceutically acceptable bases are sodium hydroxide, potassiumhydroxide, lithium hydroxide, ammonium hydroxide, calcium hydroxide,magnesium hydroxide, ferrous hydroxide, zinc hydroxide, copperhydroxide, manganous hydroxide, aluminum hydroxide, ferric hydroxide,manganic hydroxide, isopropylamine, trimethylamine, diethylamine,triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, tromethamine, lysine, arginine, histidine,caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine,glucosamine, methylglucamine, theobromine, purines, piperazine,piperidine, N-ethylpiperidine, polyamine resins and the like. Thereaction is conducted in water, alone or in combination with an inert,water-miscible organic solvent, at a temperature of from about 0° C. toabout 100° C, preferably at room temperature. Typical inert,water-miscible organic solvents include methanol, ethanol, isopropanol,butanol, acetone, dioxane or tetrahydrofuran. The molar ratio ofcompounds of Formula (A) or the (l)-acid isomers thereof to base usedare chosen to provide the ratio desired for any particular salt. Forpreparing, for example, the calcium salts or magnesium salts of thecompounds of Formula (A) or the (l)-acid isomers thereof, the free acidstarting material can be treated with at least one-half molar equivalentof pharmaceutically acceptable base to yield a neutral salt. When thealuminum salts of the compounds of Formula (A) or the (l)-acid isomersthereof are prepared at least one-third molar equivalent of thepharmaceutically acceptable base are employed if a neutral salt productis desired.

In the preferred procedure, the calcium salts and magnesium salts of thecompounds of Formula (A) and (l)-acid isomers thereof can be prepared bytreating the corresponding sodium or potassium salts thereof with atleast one-half molar equivalent of calcium chloride or magnesiumchloride, respectively, in an aqueous solution, alone or in combinationwith an inert water-miscible organic solvent, at a temperature of fromabout 20° C to about 100° C. Preferably, the aluminum salts of thecompounds hereof, can be prepared by treating the corresponding freeacids with at least one-third molar equivalent of an aluminum alkoxide,such as aluminum triethoxide, aluminum tripropoxide and the like, in ahydrocarbon solvent, such as benzene, xylene, cyclohexane and the like,at a temperature of from about 20° C to about 115° C. Similar procedurescan be used to prepare salts of inorganic bases which are notsufficiently soluble for easy reaction.

It is to be understood that isolation of the compounds described hereincan be effected, if desired, by any suitable separation or purificationprocedure, such as, for example, extraction, filtration, evaporation,distillation, crystallization, thin-layer chromatography or columnchromatography, high pressure liquid chromotography (HPLC) or acombination of these procedures. Illustrations of suitable separationand isolation procedures can be had by reference to the Examples hereinbelow. However, other equivalent separation or isolation procedurescould, of course, also be used.

While the (d)-acid isomers are not used as medicinal agents per se, theycan, if desired, be converted to their pharmaceutically acceptable,non-toxic esters and salts thereof according to the methods describedfor the conversion of the (l)-acid isomers to their pharmaceuticallyacceptable, non-toxic esters and salts thereof.

The compounds of Formula (A) and the (l)-acid isomers thereof and thepharmaceutically acceptable non-toxic esters and salts thereof, areuseful as anti-inflammatory agents, analgetic agents, plateletaggregation inhibitors, fibrinolytic agents, and as smooth musclerelaxants. These compounds can be used both prophylactically andtherapeutically.

The compositions containing these compounds are thus useful in thetreatment and elimination of inflammation such as inflammatoryconditions of the muscular skeletal system, skeletal joints and othertissues, for example, in the treatment of inflammatory conditions suchas rheumatism, consussion, laceration, arthritis, bone fractures,post-traumatic conditions, and gout. In those cases in which the aboveconditions include pain and pyrexia coupled with inflammation, theinstant compounds are useful for the relief of these conditions as wellas the inflammation.

Administration of the active compounds of Formula (A) or the (l)-acidisomers thereof and the pharmaceutically acceptable, non-toxic estersand salts thereof, in an appropriate pharmaceutical composition can bevia any of the accepted modes of administration of agents for thetreatment of inflammation, pain or pyrexia, or the prophylaxis thereof.Thus, administration can be for example, orally, parenterally ortopically, in the form of solid, semi-solid or liquid dosage forms, suchas, for example, tablets, suppositories, pills, capsules, powders,solutions, suspensions, emulsions, creams, lotions, ointments or thelike, preferably in unit dosage forms suitable for simple administrationof precise dosages. The compositions will include a conventionalpharmaceutical carrier or excipient and an active compound of Formula(A) or the (l)-acid isomer thereof and the pharmaceutically acceptablenon-toxic esters and salts thereof, and, in addition, may include othermedicinal agents, pharmaceutical agents, carriers, adjuvants, etc.

The preferred manner of administration, for the conditions detailedabove, is oral using a convenient daily dosage regimen which can beadjusted according to the degree of affliction. Generally, a daily doseof from 25 mg. to 1000 mg. of the active compound of Formula (A) or the(l)-acid isomer thereof and the pharmaceutically acceptable, non-toxicesters and salts thereof is used. Most conditions respond to treatmentcomprising a dosage level of the order of 0.5 mg. to 15 mg. per kilogramof body weight per day. For such oral administration, a pharmaceuticallyacceptable, non-toxic composition is formed by the incorporation of anyof the normally employed excipients, such as, for example,pharmaceutical grades of mannitol, lactose, starch, magnesium stearate,sodium saccarine, talcum, cellulose, glucose, gelatin, sucrose,magnesium carbonate, and the like. Such compositions take the form ofsolutions, suspensions, tablets, pills, capsules, powders, sustainedrelease formulations and the like.

The active compounds of Formula (A) or the (l)-acid isomers thereof andthe pharmaceutically acceptable, non-toxic esters and salts thereof, maybe formulated into a suppository using, for example, polyalkyleneglycols, for example, polypropylene glycol, as the carrier. Liquidpharmaceutically administerable compositions can, for example, beprepared by dissolving, dispersing, etc. an active compound, asdescribed above, and optional pharmaceutical adjuvants in a carrier,such as, for example, water, saline, aqueous dextrose, glycerol, ethanoland the like, to thereby form a solution or suspension. If desired, thepharmaceutical composition to be administered may also contain minoramounts of non-toxic auxiliary substances such as wetting or emulsifyingagents, pH buffering agents and the like, such as for example, sodiumacetate, sorbitan monolaurate, triethanolamine oleate, etc.

Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania,14th. Edition, 1970. The composition to be administered will, in anyevent, contain a quantity of the active compound(s) in apharmaceutically effective amount for relief of the particular conditionbeing treated in accordance with the teachings of this invention.

The compounds of Formula (A) and the (l)-acid isomers thereof and thenon-toxic, pharmaceutically acceptable esters and salts thereof,described above, are also uterine smooth muscle relaxants and thus areuseful as agents for maintaining the pregnancy of pregnant mammals, forthe benefit of the mother and/or fetus, until termination of thepregnancy is considered, from a medical point of view, to be favorable,or more favorable, for the mother and/or the fetus. It should beunderstood, however, that in certain instances, for example whereparturition has already begun (i.e., the mother is experiencing uterinecontractions, especially near full term), that administration of thecompounds herein described may not maintain the pregnant state for anindefinite period of time. Rather, in such instances, the pregnancywill, most probably, be slightly "prolonged", a factor which may beadvantageous to either the mother and/or the fetus.

In particular, the compounds of Formula (A) and the (l)-acid isomersthereof and the pharmaceutically acceptable, non-toxic esters and saltsthereof, are used as agents for delaying the onset of, or forpostponing, parturition. As used in this application, the phrase "todelay the onset of parturition" is intended to cover that delay inparturition caused by the administration of the compounds of Formula (A)or the (l)-acid isomers thereof and the pharmaceutically acceptable,non-toxic esters and salts thereof, at any time before uterine musclecontractions have begun. Thus, it is intended that the aforementionedphrase cover abortion prevention early in pregnancy (i.e., before thefetus is "viable") as well as delaying premature parturition, a termwhich sometimes is used with reference to that premature laborexperienced later in the pregnancy when the fetus is considered to be"viable". In either case, the agents are administered as prophylacticagents in that such administration tends to prevent the onset ofparturition. This administration is particularly useful in the treatmentof woman having a history of spontaneous abortion, miscarriage orpremature delivery (i.e., delivery prior to full term). Suchadministration is also useful where there are clinical indications thatthe pregnancy might be terminated prior to that time and is consideredfavorable to the mother and/or fetus.

With respect to animals, this treatment can also be utilized tosynchronize the deliveries from a group of pregnant animals to happen ator about the same time, or the happen at or about a desired time and/orplace, when the births can be handled with greater facility.

As used in this application, the phrase "postponing parturition" isintended to cover that delay in parturition caused by the administrationof the compounds of Formula (A) or the (l)-acid isomers thereof and thepharmaceutically acceptable, non-toxic esters and salts thereof afteruterine muscle contractions have begun. The condition of the patient,including the time within the gestation period when the contractionshave begun, the severity of the contractions and how long thecontractions have taken place will affect the results achieved with theadministration of the compounds hereof. For example, the effect can beto reduce the intensity and/or the duration of the contractions (theactual act of parturition being "prolonged"), or the stop thecontractions altogether. In either case, the effect will be to prolongthe gestation period although, depending upon the conditions of thepatient as described above, the effect may either be slight or, underappropriate circumstances, somewhat greater. Such administration may beto prevent spontaneous abortion, to cause the delivery to be more easilyaccomplished and/or less painful to the mother, or to occur at a moreappropriate time and/or place.

In all cases, administration of the compounds of Formula (A) or the(l)-acid isomers thereof and the pharmaceutically acceptable, non-toxicesters and salts thereof, for the purposes set forth herein should beconsistent with best and/or accepted medical (or veterinary) practicesso as to maximize the benefits to the mother and the fetus. For example,administration should not be continued so long past full term that thefetus dies in utero.

In the practice of the methods of the present invention, atherapeutically effective amount of a compound of Formula (A) or the(l)-acid isomers thereof and the pharmaceutically acceptable, non-toxicesters and salts thereof, or a pharmaceutical composition containingsame, is administered to the pregnant mammal via any of the usual andacceptable methods known in the art. The compound can be administeredeither singly or in combination with another compound or compounds, asdefined above, or other pharmaceutical agents, carriers, adjuvants, etc.Such compound(s) or compositions can be administered orally,parenterally, either in the form of solid, semi-solid, or liquid dosageforms. Typically, administration is by a pharmaceutical compositioncontaining the pharmaceutically active compound and one or morepharmaceutical carriers or adjuvants.

The administerable pharmaceutical composition may take the form of oraltablets, vaginal or uterine tablets or suppositories, pills, capsules,liquid solutions, suspensions, or the like, preferably in unit dosageforms suitable for simple administration of precise dosages.Conventional non-toxic solid carriers include, for example,pharmaceutical grades of mannitol, lactose, starch, magnesium stearate,sodium saccharin, talcum, cellulose, glucose, gelatin, sucrose,magnesium carbonate, and the like. The active compound as defined abovemay be formulated as suppositories using, for example, polyalkyleneglycols, for example, polypropylene glycol, as the carrier. Liquidpharmaceutically administerable compositions can, for example, beprepared by dissolving, dispersing, etc. an active compound as definedabove and optional pharmaceutical adjuvants in a carrier, such as, forexample, water, saline, aqueous dextrose, glycerol, ethanol, and thelike, to thereby form a solution or suspension. If desired, thepharmaceutical composition to be administered may also contain minoramounts of non-toxic auxiliary substances such as wetting or emulsifyingagents, pH buffering agents and the like, for example, sodium acetate,sorbitan monolaurate, triethanolamine oleate, etc. Actual methods ofpreparing such dosage forms are known, or will be apparent, to thoseskilled in this art; for example, see Remington's PharmaceuticalSciences, Mack Publishing Company, Easton, Pennsylvania, 14th Edition,1970. The composition or formulation to be administered will, in anyevent, contain a quantity of the active compound(s) in an amounteffective to delay the onset of parturition or to postpone parturitionif uterine contractions have already begun. Generally a daily dose offrom 0.5 mg. to about 25 mg. of the active compound per kilogram of bodyweight will be administered, with administration being a single dailydose or up to three or four smaller dosages regularly given throughoutthe day. The amount of active compound administered will, of course,depend on its relative activity.

The following Preparation and Examples illustrate the invention but arenot intended to limit its scope. The abbreviation t.l.c. refers tothin-layer chromatography and all mixture ratios used with regard toliquids refer to volume ratios. Also where necessary, examples arerepeated to prepare additional material for subsequent examples, andunless otherwise specified the reactions are carried out at roomtemperature (20° C to 30° C).

PREPARATION

A. A solution of 10 g. of N-methylpyrrole-2-carboxylic acid in 20 ml. ofanhydrous benzene is treated with 11.5 ml. of thionyl chloride, and thereaction mixture is refluxed under anhydrous conditions for 16 hours.The benzene and excess thionyl chloride are distilled off and theresidue is distilled under reduced pressure, to afford 7.88 g. ofN-methylpyrrole-2-carbonyl chloride, b.p. 79.84° C/5 mm.

B. Under an atmosphere of argon there are mixed 7.88 g. ofN-methylpyrrole-2-carbonyl chloride and 400 ml. of anhydrous benzene.The solution is cooled to 5° C in an ice-water bath and anhydrousdimethylamine is slowly bubbled through the solution. The temperature ofthe reaction mixture is allowed to rise to room temperature anddimethylamine is bubbled for an additional 5 minute period. The reactionmixture is then diluted with water, the organic phase is separated andwashed with 50 ml. of 10% aqueous hydrochloric acid, 50 ml. of saturatedsodium bicarbonate solution and twice with 50 ml. of saturated sodiumchloride solution. The organic extract is dried with anhydrous sodiumsulfate, decolorized with charcoal and evaporated to dryness underreduced pressure, thus obtaining 8 g. ofN,N-dimethyl-1-methylpyrrole-2-carboxamide, as an oil, which has thefollowing physical constants: U.V. λ_(max) ^(MeOH) 221, 226 nm (ε6900,9300); I.R. ν_(max) ^(CHCl).sbsp.3 1610 cm⁻¹ ; N.M.R. δ_(TMS)^(CDCl).sbsp.3 3.08 (s, 6H), 3.70 (s, 3H), 5.87-6.05 (m, 1H), 6.17-6.35(m, 1H), 6.47-6.65 ppm (m, 1-H).

By repeating the above procedures, using N-ethylpyrrole-2-carboxylicacid, N-propylpyrrole-2-carboxylic acid and N-butylpyrrole-2-carboxylicacid as starting materials there are respectively obtained:N,N-dimethyl-1-ethylpyrrole-2-carboxamide,N,N-dimethyl-1-propylpyrrole-2-carboxamide andN,N-dimethyl-1-butyl-pyrrole-2-carboxamide.

N-propylpyrrole-2-carboxylic acid and N-butylpyrrole-2-carboxylic acidare prepared by reaction of N-propylpyrrole and N-butylpyrrole withtrichloroacetyl chloride, to give the corresponding 2-trichloroacetylpyrroles, followed by base treatment, as described by A. Treibs et al.,in Liebigs Ann. Chem. 721, p. 105 (1969).

Likewise, by the method of part B of this Preparation,pyrrole-2-carbonyl chloride, obtained as described by R. J. Boatman etal., in J. Org. Chem. 41, p. 3050 (1976), is converted intoN,N-dimethylpyrrole-2-carboxamide, m.p. 100.5°-102° C.

EXAMPLE 1

A 250 ml. 3-necked round bottomed flask containing a magnetic stirringbar and fitted with a calcium chloride filled drying tube is connecteddirectly (via one of the outer necks) by means of receiver adapter andshort (3 inch) water condenser to the acetal pyrolysis apparatus. Thislatter apparatus consists of a 100 ml. round bottomed flask previouslycharged with 15.6 g. of oxalic acid dihydrate and 11.82 g. ofbromoacetaldehyde diethyl acetal, prepared from vinyl acetate, asdescribed by P. Z. Bedoukian, J. Am. Chem. Soc. 66, 651 (1944)!, toppedwith a 6 inch Vigreux column, bearing a thermometer, connected to theabove mentioned condenser.

The 3-necked flask is charged with 3.36 g. of ethanolamine cooled in anice bath at 0°-10° C and treated dropwise, with stirring, with 8.7 g. ofdimethyl 1,3-acetonedicarboxylate. Methyl3-carbomethoxymethyl-3(2'-hydroxyethyl) amino acrylate (III) formsimmediately. When the addition is completed, the ice bath is removed and100 ml. of dry acetonitrile is added. The pyrolysis part of theapparatus is placed in an oil bath and the temperature thereof is raisedto 150°-160° C. The bromoacetaldehyde solution which forms is distilled(b.p. 80°-82° C/580 mm) directly into the magnetically stirred solutionof the vinylamine (III). When the distillation temperature drops below80° C, the pyrolysis apparatus is disconnected and replaced by a refluxcondenser fitted with a drying tube containing calcium chloride. Thesolution is heated at reflux temperature for 1 hour, the solvent isremoved under reduced pressure and then 200 ml. of methanol and 20 g. ofsilica gel are added to the residue. This mixture is evaporated todryness in vacuum and placed on top of a column of 200 g. of silica gelpacked in hexane. The column is then eluted with hexane:ethyl acetate(80:20; 500 ml.) and hexane:ethyl acetate (1:1; 9 × 500 ml.). Fractions2 and 3 contain less polar impurities and dimethyl1,3-acetonedicarboxylate; fractions 4-8 afford 4.1 g. of methylN-(2-hydroxyethyl)-3-carbomethoxypyrrole-2-acetate (IV,R = H), whichupon recrystallization from ether-hexane has a melting point of 52°-54°C.

EXAMPLE 2

To a stirred solution of 4.1 g. of methylN-(2-hydroxyethyl)-3-carbomethoxypyrrole-2-acetate in 35 ml. of drydichloromethane cooled to -10° C, are added 2.65 ml. of triethylamineand thereafter, in a dropwise fashion, 1.46 ml. of methanesulfonylchloride, maintaining the temperature of the reaction mixture at -10° to-5° C. The course of the reaction is followed by t.l.c. analysis usingchloroform:acetone (90:10). When the reaction appears to be complete(about 30 minutes after the addition of the methanesulfonyl chloride isterminated) there is added slowly 10 ml. of water. The organic phase isseparated, washed with water (3 × 30 ml.), dried over sodium sulfate andevaporated under reduced pressure. Crystallization of the residue fromdichloromethane-hexane affords 4.75 g. of methylN-(2-mesyloxyethyl)-3-carbomethoxypyrrole-2-acetate (V,R = H), m.p.99°-101° C.

EXAMPLE 3

A solution of 785 mg. of methylN-(2-mesyloxyethyl)-3-carbomethoxypyrrole-2-acetate and 1.83 g. ofsodium iodide in 10 ml. of acetonitrile is refluxed for 1 hour. Thecooled reaction mixture is evaporated to dryness under reduced pressureand the residue is triturated with water. The insoluble material isseparated by filtration and air dried, thus obtaining 840 mg. of methylN-(2-iodoethyl)-3-carbomethoxypyrrole-2-acetate (VI, R = H), m.p.137°-138° C.

EXAMPLE 4

A solution of 1 g. of methylN-(2-iodoethyl)-3-carbomethoxypyrrole-2-acetate in 5 ml. of drydimethylformamide is stirred, under an atmosphere of argon, with 137 mg.of 50% sodium hydride in mineral oil. The reaction mixture is maintainedfor 30 minutes at room temperature and then quenched with 100 ml. ofwater. The product is extracted with ethyl acetate (3 × 50 ml.), thecombined extracts are washed with water, dried over magnesium sulfateand evaporated to dryness. Chromatography of the residue on 20 g. ofsilica gel, using hexane:ethyl acetate (4:1) as eluant, affords 500 mg.of dimethyl 1,2-dihydro-3H-pyrrolo 1,2-a!pyrrole-1,7-dicarboxylate (VII,R = H) m.p. 70°-71° C.

A solution of 1.80 g. of dimethyl 1,2-dihydro-3H-pyrrolo1,2-a!pyrrole-1,7-dicarboxylate in 20 ml. of methanol is treated with asolution of 4.48 g. of potassium hydroxide in 20 ml. of water, and thereaction mixture is refluxed for 6 hours. The cooled solution isevaporated to dryness and the residue is treated with 50 ml. ofsaturated sodium chloride solution. The resultant solution is acidifiedwith 6N hydrochloric acid and extracted with ethyl acetate (3 × 50 ml.).The combined extracts are dried over magnesium sulfate and evaporated todryness under reduced pressure, to yield 1.51 g. of1,2-dihydro-3H-pyrrolo 1,2-a!pyrrole-1,7-dicarboxylic acid (VIII, R =H), m.p. 220° C, with decomposition.

EXAMPLE 5

A solution of 1.34 g. of 1,2-dihydro-3H-pyrrolo1,2-a!pyrrole-1,7-dicarboxylic acid in 50 ml. of isopropanol, cooled inan ice bath is saturated with gaseous hydrogen chloride, maintaining thetemperature of the reaction mixture below 50° C. The ice bath is thenremoved and the reaction mixture is stirred for 1.5 hours at roomtemperature, and evaporated to dryness under reduced pressure; 10 ml. ofbenzene is added to the residue and the solution is evaporated undervacuum once again, repeating this process a total of three times tocompletely remove the excess hydrogen chloride, thus obtaining 1.58 g.of isopropyl 1,2-dihydro-3H-pyrrolo1,2-a!pyrrole-1-carboxylate-7-carboxylic acid (IX, R = H, R² = iC₃ H₇),which upon crystallization from methanol-ethyl acetate has a meltingpoint of 144°-145° C.

In a similar manner but substituting methanol, ethanol, propanol andn-butanol for isopropanol in the above procedure there are respectivelyobtained:

methyl 1,2-dihydro-3H-pyrrolo 1,2-a!pyrrole-1-carboxylate-7-carboxylicacid,

ethyl 1,2-dihydro-3H-pyrrolo 1,2-a!pyrrole-1-carboxylate-7-carboxylicacid,

propyl 1,2-dihydro-3H-pyrrolo 1,2-a!pyrrole-1-carboxylate-7-carboxylicacid, and

butyl 1,2-dihydro-3H-pyrrolo 1,2-a!pyrrole-1-carboxylate-7-carboxylicacid.

EXAMPLE 6

1.054 G. of isopropyl 1,2-dihydro-3H-pyrrolo1,2-a!pyrrole-1-carboxylate-7-carboxylic acid is heated to 240°-250° Cin a dry 10 ml. round bottomed flask, distilling directly the reactionproduct from the reaction vessel. In this manner there is obtained 745mg. of isopropyl-1,2-dihydro-3H-pyrrolo 1,2-a!pyrrole-1-carboxylate (X,R = H, R² = iC₃ H₇), a pale yellow oil, having the following physicalconstants: U.V.: .sub.λmax^(MeOH) 215 nm (ε 6020); I.R.:.sub.νmax^(CHCl).sbsp.3 1725 cm⁻¹ ; N.M.R.: .sub.δTMS^(CDCl).sbsp.3 1.22(d, J = Hz, 6H), 2.40-2.90 (m, 2H), 3.60-4.20 (m, 2H), 4.65-5.2 (m, 1H),5.73-5.92 (m, 1H), 6.10 (t, J = 3 Hz, 1H), 6.43-6.53 ppm. (m, 1H).

EXAMPLE 7

A 100 ml. 3-necked round bottomed flask equipped with a condenser,nitrogen inlet tube and a gas bubbler is charged with 5.0 g. ofisopropyl 1,2-dihydro-3 H-pyrrolo1,2-a!pyrrole-1-carboxylate-7-carboxylic acid. The apparatus isthoroughly flushed with nitrogen and then the nitrogen flow is stopped.The apparatus is immersed in an oil bath heated at 270° C and thereaction is followed by the rate of carbon dioxide evolution (gasbubbler) and by t.l.c. on silica gel, using benzene:dioxan:acetic acid(90:10:1) as developing solvent. After 45 minutes the reaction is almostcomplete. After one hour, the vessel is removed from the oil bath andthe contents of the reaction flask are transferred to a round bottomedflask with 500 ml. of acetone. The solvent is removed under reducedpressure, and the residue is purified by column chromatography on 100 g.of silica gel. The fractions eluted with hexane:benzene (70:30) andhexane:bezene (50:50) afford 2.77 g. of isopropyl 1,2-dihydro-3H-pyrrolo1,2-a!pyrrole-1-carboxylate (X, R = H, R² = iC₃ H₇), an oil, whosephysical constants are identical to those obtained in Example 6.

EXAMPLE 8

A solution of 204 mg. of N,N-dimethyl-1-methylpyrrole-2-carboxamide in10 ml. of anhydrous dichloromethane containing 307 mg. of phosphorousoxychloride is refluxed for 30 minutes under an argon atmosphere. Tothis solution is added a solution of 193 mg. of isopropyl1,2-dihydro-3H-pyrrolo 1,2-a!pyrrole-1-carboxylate in 15 ml. of1,2-dichloroethane. The reaction mixture is refluxed under an argonatmosphere for 50 hours, cooled to room temperature and treated with asolution of 1.36 g. of sodium acetate dissolved in 15 ml. of water. Theresultant mixture is refluxed for 30 minutes furthur, and then cooled,the organic phase is separated and the aqueous phase extracted withchloroform. The combined organic solutions are washed with saturatedsodium chloride solution (2 × 10 ml.), dried with anhydrous sodiumsulfate and evaporated to dryness under reduced pressure. The oilyresidue is purified by t.l.c. using ethyl acetate:methylene chloride(3:97) as eluant, to yield 253 mg. of isopropyl5-(N-methyl-2-pyrroyl)-1,2 -dihydro-3H-pyrrolo1,2-a!-pyrrole-1-carboxylate (XI, R = H, R¹ = CH₃, R² = iC₃ H₇), a paleyellow oil, having the following physical constants: U.V..sub.λmax^(MeOH) 260-275 (shoulder), 330 nm (ε 4790, 19500); I.R..sub.νmax^(CHCl).sbsp.3 1735, 1600 cm⁻¹ ; N.M.R. .sub.δTMS^(CDCl).sbsp.31.27 (d, 6H J = 6 Hz), 2.50-3.10 (m, 2H), 3.85 (s, 3H), 3.92 (dd, 1H,J_(AX) = 6 Hz, J_(BX) = 7 Hz; H-1), 4.17-4.60 (m, 2H), 4.95 (sept., 1H,J = 6 Hz), 5.85-6.20 (m, 2H), 6.60-7.87 ppm (m, 3H), M.S. m/e 300 (M⁺).

EXAMPLE 9

A mixture of 1.2 g. of isopropyl5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo1,2-a!pyrrole-1-carboxylate, 1.1 g. of potassium carbonate and 25 ml. ofa (4:1) methanol-water mixture is refluxed under nitrogen atmosphere for30 minutes, cooled, and evaporated to dryness. The residue is taken upin 50 ml. of water and extracted with ethyl acetate (3 × 10 ml.). Theaqueous solution is acidified with 10% hydrochloric acid and extractedwith ethyl acetate (10 × 15 ml.). The combined extracts are washed withsaturated sodium chloride solution dried with anhydrous sodium sulfateand evaporated to dryness under reduced pressure. Crystallization of theresidue from methylene chloride-ether-hexane affords 636 mg. of5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo 1,2-a!pyrrole-1-carboxylicacid, (A), R = H, R¹ - CH₃ !, m.p. 161°-161.5° C.

EXAMPLE 10

By following the methods of Examples 6 or 7, the remaining compoundsobtained in Example 5 are converted respectively into:

methyl 1,2-dihydro-3H-pyrrolo 1,2-a!pyrrole-1-carboxylate,

ethyl 1,2-dihydro-3H-pyrrolo 1,2-a!pyrrole-1-carboxylate,

propyl 1,2-dihydro-3H-pyrrolo 1,2-a!pyrrole-1-carboxylate, and

butyl 1,2-dihydro-3H-pyrrolo 1,2-a!pyrrole-1-carboxylate.

Upon condensation of these compounds withN,N-dimethyl-1-methylpyrrole-2-carboxamide, in accordance with themethod of Example 8, there are respectively obtained.

methyl 5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo1,2-a!pyrrole-1-carboxylate,

ethyl 5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo1,2-a!pyrrole-1-carboxylate,

propyl 5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo1,2-a!pyrrole-1-carboxylate and

butyl 5-(N-methyl-2-pyrroyl)-1-2-dihydro-3H-pyrrolo1,2-a!pyrrole-1-carboxylate.

EXAMPLE 11

Example 8 is repeated using 1.5 molar equivalents of

N,N-dimethylpyrrole-2-carboxamide,

N,N-dimethyl-1-ethylpyrrole-2-carboxamide,

N,N-dimethyl-1-propylpyrrole-2-carboxamide and

N,N-dimethyl-1-butylpyrrole-2-carboxamide in place ofN,N-dimethyl-1-methylpyrrole-2-carboxamide, thus obtaining respectively:

isopropyl 5-(2-pyrroyl)-1,2-dihydro-3H-pyrrolo 1,2-a!pyrrole-1-carboxylate, m.p. 131.5°-132.5° C,

isopropyl 5-(N-ethyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo1,2-a!pyrrole-1-carboxylate,

isopropyl 5-(N-propyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo1,2-a!pyrrole-1-carboxylate and

isopropyl 5-(N-butyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo1,2-a!pyrrole-1-carboxylate.

Upon hydrolysis of the isopropyl ester group, in accordance with themethod of Example 9, there are obtained the corresponding free acids,namely:

5-(2-pyrroyl)-1,2-dihydro-3H-pyrrolo 1,2-a!pyrrole-1-carboxylic acid,m.p. 217°-218° C,

5-(N-ethyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo 1,2-a!pyrrole-1-carboxylicacid,

5-(N-propyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo 1,2-a!pyrrole-1-carboxylicacid and

5-(N-butyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo 1,2-a!pyrrole-1-carboxylicacid.

EXAMPLE 12

A 250 ml. 3-necked round bottomed flask containing a magnetic stirringbar and fitted with a calcium chloride filled drying tube, is chargedwith 3.36 g. of ethanolamine cooled in an ice bath at 0° C and treateddropwise, with stirring, with 8.7 g. of dimethyl1,3-acetone-dicarboxylate. Methyl3-carbomethoxymethyl-3-(2'-hydroxyethyl)amino acrylate (III) formsimmediately. When the addition is completed, the ice bath is removed and80 ml. of dry acetonitrile is added. The reaction mixture is thentreated dropwise with 6.75 g. of bromoacetaldehyde in 20 ml. ofacetonitrile and thereafter heated at reflux temperature for 2 hours.The solvent is then removed under reduced pressure and 200 ml. ofmethanol and 20 g. of silica gel are added to the residue. This mixtureis evaporated to dryness in vacuum and placed on top of a column of 200g. of silica gel packed in hexane, eluting the column with hexane:ethylacetate mixtures. The fractions eluted with hexane:ethyl acetate (1:1)afford methyl N-(2 -hydroxyethyl)-3-carbomethoxypyrrole-2-acetate (IV, R= H) identical to the product obtained in Example 1.

EXAMPLE 13

To a solution of 6 ml. of ethanolamine in 5 ml. of water there is addedin one portion, 1.74 g. of dimethyl 1,3-acetonedicarboxylate. Theresultant mixture is rapidly cooled to -10° C and treated dropwise overa 15 minute period, with stirring, with 1.67 ml. of 1-bromo-acetone,whilst maintaining the reaction mixture at a temperature not higher than40° C. When the addition is completed the dark reaction mixture isstirred for an additional hour at room temperature, and then poured intoa mixture of hydrochloric acid-ice, saturated with solid sodium chlorideand extracted with ethyl acetate (3 × 100 ml.). The combined organicextract is washed with cold water to neutrality, dried with anhydroussodium sulfate and evaporated to dryness under reduced pressure.Chromatography of the residue on 30 g. of silica gel, using hexane:ethylacetate (70:30) as eluant, affords 890 mg. of crystalline methylN-(2-hydroxyethyl)-3-carbomethoxy-4-methylpyrrole-2-acetate (IV, R =CH₃), which upon recrystallization from methylene chloride-hexane meltsat 78° C.

In a similar manner, substituting 1-bromo-2-butanone,1-bromo-2-pentanone, 1-bromo-2-hexanone or the corresponding 1-chloroderivatives for 1-bromoacetone, there are respectively obtained:

methyl N-(2-hydroxyethyl)-3-carbomethoxy-4-ethylpyrrole-2-acetate,

methyl N-(2-hydroxyethyl)-3-carbomethoxy-4-propylpyrrole-2-acetate and

methyl N-(2-hydroxyethyl)-3-carbomethoxy-4-butylpyrrole-2-acetate.

EXAMPLE 14

To a stirred solution of 7.7 g. of methylN-(2-hydroxyethyl)-3-carbomethoxy-4-methylpyrrole-2-acetate in 200 ml.of dry dichloromethane cooled to 0° C, are added 4.24 ml. oftriethylamine and 2.4 ml. of methanesulfonyl chloride. The reactionmixture is kept at room temperature for 15 minutes and then diluted withwater. The organic phase is separated, washed with water (3 × 30 ml.)dried over anhydrous sodium sulfate and evaporated to dryness underreduced pressure. Crystallization of the residue from methanol affords9.04 g. of methylN-(2-mesyloxyethyl)-3-carbomethoxy-4-methylpyrrole-2-acetate (V, R =CH₃), m.p. 81° C.

A solution of 9.067 g. of methylN-(2-mesyloxyethyl)-3-carbomethoxy-4-methylpyrrole-2-acetate in 250 ml.of dry acetonitrile is treated with 20.23 g. of sodium iodide, and theresultant mixture is refluxed for 8 hours. The solvent is thenevaporated to dryness under reduced pressure and the residue taken up in100 ml. of dichloromethane. The organic solution is washed with water (2× 40 ml.), dried with anhydrous sodium sulfate, and evaporated todryness under reduced pressure. Crystallization of the solid residuefrom hexane-ether affords 9.13 g. of methylN-(2-iodoethyl)-3-carbomethoxy-4-methyl-pyrrole-2-acetate (VI, R = CH₃),m.p. 103° C.

EXAMPLE 15

To a stirred suspension of 660 mg. of sodium hydride in 250 ml. of drydimethylformamide, cooled to 0° C and maintained in an atmosphere ofnitrogen, there are added 9.13 g. of methylN-(2-iodoethyl)-3-carbomethoxy-4-methylpyrrole-2-acetate. The reactionmixture is stirred for 3 hours at room temperature and then quenchedwith 250 ml. of water. The product is extracted with benzene (3 × 100ml.), the combined extracts are washed with water (2 × 100 ml.), driedover anhydrous sodium sulfate and evaporated to dryness under reducedpressure. Chromatography of the residue on 200 g. of silica gel, usinghexane:ethyl acetate (70:30) as eluant, affords 4.56 g. of dimethyl1,2-dihydro-6-methyl-3H-pyrrolo 1,2-a!pyrrole-1,7-dicarboxylate (VII, R= CH₃) which is recrystallized from ether-hexane, m.p. 71° C.

A solution of 3.81 g. of dimethyl 1,2-dihydro-6-methyl-3H-pyrrolo1,2-a!pyrrole-1,7-dicarboxylate in 30 ml. of methanol is treated with asolution of 8.96 g. of potassium hydroxide in 15 ml. of water, and thereaction mixture is refluxed for 8 hours. The methanol is theneliminated under vacuum, the aqueous solution is cooled to 0° C andacidified with 20% hydrochloric acid. The formed precipitate iscollected by filtration, washed with water, dried in an oven andrecrystallized from methanol, thus obtaining 2.55 g. of1,2-dihydro-6-methyl-3H-pyrrolo- 1,2-a!pyrrole-1,7-dicarboxylic acid(VIII, R = CH₃), m.p. 200°-230° C with decomposition.

EXAMPLE 16

A solution of 3.8 g. of 1,2-dihydro-6-methyl-3H-pyrrolo1,2-a!pyrrole-1,7-dicarboxylic acid in 100 ml. of freshly distilledisopropanol is cooled to -10° C and saturated with gaseous hydrogenchloride. The ice bath is then removed and the reaction mixture isstirred for 3 hours at room temperature, and thereafter evaporated todryness under reduced pressure. The residue is dissolved in 100 ml. ofethyl acetate and the solution is washed with saturated sodium chloridesolution (2 × 100 ml.) dried over anhydrous sodium sulfate andevaporated to dryness under reduced pressure. Crystallization of theresidue from acetone-water affords 3.74 g. of isopropyl1,2-dihydro-6-methyl-3H-pyrrolo 1,2-a!pyrrole-1-carboxylate-7-carboxylic acid (IX, R = CH₃, R² = iC₃ H₇), m.p. 160° C.

Eight grams of isopropyl 1,2-dihydro-6-methyl-3H-pyrrolo1,2-a!pyrrole-1-carboxylate-7-carboxylic acid is heated to 240° (ca. 1h) in an apparatus assembled for distillation. A light yellow oildistills as the decarboxylation proceeds, thus obtaining 4.61 g. ofisopropyl 1,2-dihydro-6-methyl-3H-pyrrolo 1,2-a!pyrrole-1-carboxylate(X, R = CH₃, R² = iC₃ H₇). This substance is very unstable in air atroom temperature and it should be used immediately in the next step. Ithas the following physical constants: U.V. .sub.λmax^(MeOH) 226, 250(shoulder) nm. (ε 4900, 2240); I.R. .sub.νmax^(CHCl).sbsp.3 1717 cm⁻¹ ;N.M.R. .sub.δTMS^(CDCl).sbsp.3 1.22 (d, 6H, J = 6 Hz; ester CH₃), 2.03(s, 3H; ring CH₃), 2.42-2.93 (m, 2H; CH₂), 3.55-4.17 (m, 3H; NCH₂,CHCO), 4.92 (sept., 1H, J = 6 Hz; CH of ester), 5.66 (s, 1H; H-3), 6.25(s, 1H; H-5);

    ______________________________________                                        MS      m/e       I%                                                                  207       18        M+                                                        120       100       M.sup.30 -CO.sub.2 CH(CH.sub.3).sub.2.            ______________________________________                                    

EXAMPLE 17

In accordance with the method of Example 8, isopropyl1,2-dihydro-6-methyl-3H-pyrrolo 1,2-a!pyrrole-1-carboxylate is condensedwith N,N-dimethyl-1-methylpyrrole-2-carboxamide, to produce isopropyl5-(N-methyl-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo1,2-a!pyrrole-1-carboxylate (XI, R and R¹ = CH₃, R² = iC₃ H₇).

In a similar manner but using the N,N-dimethylpyrrole-2-carboxamideslisted in Example 11 in place ofN,N-dimethyl-1-methylpyrrole-2-carboxamide, there are respectivelyobtained:

isopropyl 5-(2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo1,2-a!pyrrole-1-carboxylate,

isopropyl 5-(N-ethyl-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo1,2-a!pyrrole-1-carboxylate,

isopropyl 5-(N-propyl-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo1,2-a!pyrrole-1-carboxylate and

isopropyl 5-(N-butyl-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo1,2-a!pyrrole-1-carboxylate.

EXAMPLE 18

By following the methods of Examples 14, 15 and 16 but using methylN-(2-hydroxyethyl)-3-carboxymethoxy-4-ethylpyrrole-2-acetate, methylN-(2-hydroxyethyl)-3-carbomethoxy-4-propylpyrrole-2-acetate and methylN-(2-hydroxyethyl)-3-carbomethoxy-4-butylpyrrole-2-acetate as startingmaterials in place of methylN-(2-hydroxyethyl)-3-carbomethoxy-4-methylpyrrole-2-acetate there arerespectively obtained as final products:

isopropyl 1,2-dihydro-6-ethyl-3H-pyrrolo 1,2-a!pyrrole-1-carboxylate,

isopropyl 1,2-dihydro-6-propyl-3H-pyrrolo 1,2-a!pyrrole-1-carboxylateand

isopropyl 1,2-dihydro-6-butyl-3H-pyrrolo 1,2-a!pyrrole-1-carboxylate.

EXAMPLE 19

By following the method of Example 8, the compounds obtained in Example18 are condensed with the N,N-dimethyl-2-pyrrolamide reagents ofExamples 8 and 11, to produce the corresponding 5-pyrroyl derivatives.Representative compounds thus obtained are:

isopropyl 5-(N-methyl-2-pyrroyl)-1,2-dihydro-6-ethyl-3H-pyrrolo1,2-a!pyrrole-1-carboxylate,

isopropyl 5-(2-pyrroyl)-1,2-dihydro-6-propyl-3H-pyrrolo1,2-a!pyrrole-1-carboxylate,

isopropyl 5-(N-ethyl-2-pyrroyl)-1,2-dihydro-6-butyl-3H-pyrrolo1,2-a!pyrrole-1-carboxylate,

isopropyl 5-(N-propyl-2-pyrroyl)-1,2-dihydro-6-ethyl-3H-pyrrolo1,2-a!pyrrole-1-carboxylate,

isopropyl 5-(N-butyl-2-pyrroyl)-1,2-dihydro-6-propyl-3H-pyrrolo1,2-a!pyrrole-1-carboxylate,

isopropyl 5-(N-methyl-2-pyrroyl)-1,2-dihydro-6-butyl-3H-pyrrolo1,2-a!pyrrole-1-carboxylate and

isopropyl 5-(2-pyrroyl)-1,2-dihydro-6-ethyl-3H-pyrrolo1,2-a!pyrrole-1-carboxylate.

EXAMPLE 20

A solution of 500 mg. of isopropyl5-(N-methyl-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo1,2-a!-pyrrole-1-carboxylate in 15 ml. of methanol is treated with asolution of 1.05 g. of potassium carbonate in 8 ml. of water. Thereaction mixture is refluxed under nitrogen atmosphere for 30 minutes,cooled, and evaporated to dryness. The residue is taken up in 10 ml. of10% aqueous hydrochloric acid and 50 ml. of water and the resultantmixture extracted with ethyl acetate (3 × 50 ml.). The combined extractsare dried over magnesium sulfate and evaporated to dryness under reducedpressure, to give 5-(N-methyl-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo1,2-a!pyrrole-1-carboxylic acid (A), R and R¹ = CH₃ !.

In a similar manner the remaining isopropyl ester compound obtained inExample 17 and the compounds of Example 19 are converted into thecorresponding free acids, namely:

5-(2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo 1,2-a!pyrrole-1-carboxylicacid,

5-(N-ethyl-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo-1,2-a!pyrrole-1-carboxylic acid,

5-(N-propyl-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo-1,2-a!pyrrole-1-carboxylic acid,

5-(N-butyl-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo-1,2-a!pyrrole-1-carboxylic acid,

5-(N-methyl-2-pyrroyl)-1,2-dihydro-6-ethyl-3H-pyrrolo-1,2-a!pyrrole-1-carboxylic acid,

5-(N-ethyl-2-pyrroyl)-1,2-dihydro-6-ethyl-3H-pyrrolo-1,2-a!pyrrole-1-carboxylic acid,

5-(2-pyrroyl)-1,2-dihydro-6-propyl-3H-pyrrolo-1,2-a!pyrrole-1-carboxylic acid,

5-(N-ethyl-2-pyrroyl)-1,2-dihydro-6-butyl-3H-pyrrolo-1,2-a!pyrrole-1-carboxylic acid,

5-(N-propyl-2-pyrroyl)-1,2-dihydro-6-ethyl-3H-pyrrolo-1,2-a!pyrrole-1-carboxylic acid,

5-(N-butyl-2-pyrroyl)-1,2-dihydro-6-propyl-3H-pyrrolo-1,2-a!pyrrole-1-carboxylic acid,

5-(N-methyl-2-pyrroyl)-1,2-dihydro-6-butyl-3H-pyrrolo-1,2-a!pyrrole-1-carboxylic acid, and

5-(2-pyrroyl)-1,2-dihydro-6-ethyl-3H-pyrrolo 1,2-a!-pyrrole-1-carboxylicacid.

EXAMPLE 21

A solution of 200 mg. of5-(N-methyl-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo1,2-a!pyrrole-1-carboxylic acid in 5 ml. of methylene chloride istreated with an excess of ethereal diazomethane, and the reactionmixture is maintained at room temperature for 30 minutes. The solventsand excess reagent are eliminated under reduced pressure and the residuecrystallized from ethyl acetate-methanol, to yield methyl5-(N-methyl-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo1,2-a!pyrrole-1-carboxylate.

Likewise but using diazoethane and diazopropane in place of diazomethanethere are respectively obtained ethyl5-(N-methyl-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo 1,2-a!pyrrole-1-carboxylate and propyl5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo1,2-a!pyrrole-1-carboxylate.

In a similar manner, the remaining free acids obtained in Example 20 andthe acids of Example 11, are converted into the corresponding methyl,ethyl and propyl esters.

EXAMPLE 22

A solution of 300 mg. of 5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo1,2-a!pyrrole-1-carboxylic acid in 5 ml. of isoamyl alcohol is saturatedwith hydrogen chloride. After 24 hours, the excess alcohol is distilledoff in vacuo and the residue purified by chromatography on alumina, toyield isoamyl 5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo1,2-a!pyrrole-1-carboxylate.

Likewise other esters, e.g., pentyl, hexyl, octyl, nonyl, dodecyl, andthe like, of 5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo1,2-a!pyrrole-1-carboxylic acid are obtained by substituting otheralcohols, e.g., pentyl, hexyl, octyl, nonyl, dodecyl alcohol and thelike, for isoamyl alcohol.

By the same method the free acid compounds obtained in Examples 11 and20 are esterified with the appropriate alcohol, thus obtaining thecorresponding esters, e.g.,

pentyl 5-(2-pyrroyl)-1,2-dihydro-3H-pyrrolo 1,2-a!pyrrole-1-carboxylate,

hexyl 5-(N-ethyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo-1,2-a!pyrrole-1-carboxylate,

octyl 5-(N-propyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo-1,2-a!pyrrole-1-carboxylate

dodecyl 5-(N-butyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo1,2-a!pyrrole-1-carboxylate,

isoamyl 5-(N-methyl-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo1,2-a!pyrrole-1-carboxylate,

nonyl 5-(N-ethyl-2-pyrroyl)-1,2-dihydro-6-ethyl-3H-pyrrolo1,2-a!pyrrole-1-carboxylate,

isoamyl 5-(N-methyl-2-pyrroyl)-1,2-dihydro-6-ethyl-3H-pyrrolo1,2-a!pyrrole-1-carboxylate,

pentyl 5-(N-ethyl-2-pyrroyl)-1,2-dihydro-6-butyl-3H-pyrrolo1,2-a!pyrrole-1-carboxylate,

hexyl 5-(N-propyl-2-pyrroyl)-1,2-dihydro-6-ethyl-3H-pyrrolo1,2-a!pyrrole-1-carboxylate, and

dodecyl 5-(N-butyl-2-pyrroyl)-1,2-dihydro-6-propyl-3H-pyrrolo1,2-a!pyrrole-1-carboxylate.

EXAMPLE 23

To a solution of 300 mg. of 5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo 1,2-a!pyrrole-1-carboxylic acid in 5 ml. of methanolis added 1 molar equivalent of sodium hydroxide, in the form of a 0.1Nsolution. The solvent is then evaporated under reduced pressure and theresidue taken up in 2 ml. of methanol, followed by precipitation withether, to yield crude sodium 5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo- 1,2-a!pyrrole-1-carboxylate whichcan be crystallized from ethyl acetate-hexane.

Likewise other salts, e.g., ammonium and potassium of5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo-1,2-a!pyrrole-1-carboxylic acid are prepared by substituting ammoniumhydroxide and potassium hydroxide for sodium hydroxide.

In a similar manner, the 5-substituted-1,2-dihydro-3H-pyrrolo1,2-a!pyrrole-1-carboxylic acid compounds obtained in Examples 11 and 20can be converted into the corresponding sodium, potassium and ammoniumsalts.

Representative compounds thus obtained are:

sodium 5-(2-pyrroyl)-1,2-dihydro-3H-pyrrolo1,2-a!-pyrrole-1-carboxylate,

sodium 5-(N-ethyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo-1,2-a!pyrrole-1-carboxylate,

potassium 5-(N-propyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo-1,2-a!pyrrole-1-carboxylate

ammonium 5-(N-butyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo-1,2-a!pyrrole-1-carboxylate,

sodium 5-(2-pyrroyl)-1,2-dihydro-6methyl-3H-pyrrolo-1,2-a!pyrrole-1-carboxylate,

sodium 5-(N-methyl-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo1,2-a!pyrrole-1-carboxylate,

ammonium 5-(N-ethyl-2-pyrroyl)-1,2-dihydro-6-butyl-3H-pyrrolo1,2-a!pyrrole-1-carboxylate,

potassium 5-(2-pyrroyl)-1,2-dihydro-6-propyl-3H-pyrrolo1,2-a!pyrrole-1-carboxylate,

sodium 5-(N-propyl-2-pyrroyl)-1,2-dihydro-6-ethyl-3H-pyrrolo1,2-a!pyrrole-1-carboxylate,

potassium 5-(N-butyl-2-pyrroyl)-1,2-dihydro-6-propyl-3H-pyrrolo1,2-a!pyrrole-1-carboxylate, and

ammonium 5-(2-pyrroyl)-1,2-dihydro-6-ethyl-3H-pyrrolo-1,2-a!pyrrole-1-carboxylate.

EXAMPLE 24

To a solution of 175 mg. of5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo 1,2-a!pyrrole-1-carboxylicacid in 5 ml. of methanol is added 1 molar equivalent of potassiumhydroxide, in the form of a 0.1N solution, thus yielding a solutioncontaining potassium 5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo1,2-a!pyrrole-1-carboxylate. A solution of 40 mg. of calcium carbonatedissolved in the minimum amount of 1N hydrochloric acid necessary toeffect solution of the calcium carbonate, is buffered with 100 mg. ofsolid ammonium chloride, followed by the further addition of 5 ml. ofwater. The thus obtained buffered calcium solution is then added to thesolution of potassium 5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo-1,2-a!pyrrole-1-carboxylate and the precipitate which forms is collectedby filtration, washed with water and air dried, to yield calcium5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo1,2-a!pyrrole-1-carboxylate.

Likewise, magnesium 5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo1,2-a!pyrrole-1-carboxylate is prepared by substituting magnesiumcarbonate for calcium carbonate.

Similarly, by substituting 5-(2-pyrroyl)-1,2-dihydro-3H-pyrrolo1,2-a!pyrrole-1-carboxylic acid,

5-(N-ethyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo 1,2-a!-pyrrole-1-carboxylicacid,

5-(N-propyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo1,2-a!-pyrrole-1-carboxylic acid,

5-(N-butyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo 1,2-a!-pyrrole-1-carboxylicacid,

5-(N-methyl-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo-1,2-a!pyrrole-1-carboxylic acid,

5-(N-propyl-2-pyrroyl)-1,2-dihydro-6-ethyl-3H-pyrrolo-1,2-a!pyrrole-1-carboxylic acid, for

5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo1,2-a!-pyrrole-1-carboxylic acid, there are obtained the correspondingcalcium and magnesium salts.

EXAMPLE 25

A solution of 200 mg. of 5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo1,2-a!pyrrole-1-carboxylic acid in 15 ml. of hot benzene is treated with60 mg. of isopropylamine. The solution is allowed to cool to roomtemperature and the product filtered off, washed with ether and dried,to yield the isopropylamine salt of5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo 1,2-a!pyrrole-1-carboxylicacid.

Likewise other amine salts, e.g., diethylamine, ethanolamine,piperidine, tromethamine, choline and caffeine salts of5-(N-methyl-2-pyrroyl),-1,2-dihydro-3H-pyrrolo1,2-a!-pyrrole-1-carboxylic acid are prepared by substituting each ofthe respective amines for isopropylamine.

In a similar manner the free acid compounds obtained in Examples 11 and20 can be converted into the corresponding isopropylamine, diethylamine,ethanolamine, piperidine, tromethamine, choline and caffeine salts.

EXAMPLE 26

A solution of 770 mg. of 5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo1,2-a!pyrrole-1-carboxylic acid in 10 ml. of benzene is treated with 580mg. of dicyclohexylamine. The reaction mixture is stirred for 10minutes, and the solid which forms is separated by filtration and washedwith anhydrous ether thus obtaining 965 mg. of the dicyclohexylaminesalt of 5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo 1,2-a!pyrrole-1-carboxylic acid.

In a similar manner the free acid compounds obtained in Examples 11 and20 can be converted into the corresponding dicyclohexylamine salts.

EXAMPLE 27

    ______________________________________                                        Ingredients       Quantity per tablet, mgs.                                   ______________________________________                                        5-(2-pyrroyl)-1,2-dihydro-                                                    3H-pyrrolo- 1,2-a!pyrrole-                                                    1-carboxylic acid 25                                                          cornstarch        20                                                          lactose, spray-dried                                                                            153                                                         magnesium stearate                                                                              2                                                           ______________________________________                                    

The above ingredients are thoroughly mixed and pressed into singlescored tablets.

EXAMPLE 28

    ______________________________________                                        Ingredients        Quantity per tablet, mgs.                                  ______________________________________                                        5-(N-methyl-2-pyrrol)-1,2-                                                    dihydro-3H-pyrrolo- 1,2-a!-                                                   pyrrole-1-carboxylic acid                                                                        200                                                        cornstarch         50                                                         lactose            145                                                        magnesium stearate 5                                                          ______________________________________                                    

The above ingredients are mixed intimately and pressed into singlescored tablets.

100 Mg. of (l)- 5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-1,2-a!pyrrole-1-carboxylic acid is substituted for the 200 mg. of the(dl) compound of the above composition.

EXAMPLE 29

    ______________________________________                                        Ingredients        Quantity per capsule, mgs.                                 ______________________________________                                        sodium 5-(N-methyl-2-pyrroyl)                                                 1,2-dihydro-3H-pyrrolo-                                                        1,2-a!pyrrole-1-carboxylate                                                                     108                                                        lactose            15                                                         cornstarch         25                                                         magnesium stearate 2                                                          ______________________________________                                    

The above ingredients are mixed and introduced into a hard-shell gelatincapsule.

EXAMPLE 30

    ______________________________________                                        Ingredients        Quantity per capsule, mgs.                                 ______________________________________                                        calcium 5-(N-methyl-2-pyrroyl)-                                               1,2-dihydro-3H-pyrrolo-                                                        1,2-a!pyrrole-1-carboxylate                                                                     115                                                        lactose            93                                                         cornstarch         40                                                         magnesium stearate 2                                                          ______________________________________                                    

The above ingredients are mixed and introduced into a hard-shell gelatincapsule.

EXAMPLE 31

    ______________________________________                                        Ingredients         Quantity per tablet, mgs.                                 ______________________________________                                        isopropylammonium 5-(N-methyl-                                                2-pyrroyl)-1,2-dihydro-3H-                                                    pyrrolo- 1,2-a!pyrrole-1-                                                     carboxylate         245                                                       cornstarch          75                                                        lactose             175                                                       magnesium stearate  5                                                         ______________________________________                                    

The above ingredients are mixed intimately and pressed into singlescored tablets.

EXAMPLE 32

    ______________________________________                                        Ingredients      Quantity per capsule, mgs.                                   ______________________________________                                        isopropyl 5-(N-methyl-2-                                                      pyrroyl)-1,2-dihydro-3H-                                                      pyrrolo- 1,2-a!pyrrole-1-                                                     carboxylate      25                                                           lactose          125                                                          ______________________________________                                    

The above ingredients are mixed and introduced into a No. 1 hard-shellgelatin capsule.

EXAMPLE 33

    ______________________________________                                        Ingredients        Quantity per tablet, mgs.                                  ______________________________________                                        5-(N-methyl-2-pyrroyl)-1,2-                                                   dihydro-3H-pyrrolo- 1,2-a!-                                                   pyrrole-1-carboxylic acid                                                                        300                                                        sucrose            300                                                        ______________________________________                                    

The above ingredients are thoroughly mixed and processed into singlescored tablets, one tablet being administered every three to four hours.

EXAMPLE 34

    ______________________________________                                        Ingredients         Quantity per tablet, mgs.                                 ______________________________________                                        isoamyl 5-(N-methyl-2-pyrroyl)-                                               1,2-dihydro-3H-pyrrolo- 1,2-a!-                                               pyrrole-1-carboxylate                                                                             254                                                       cornstarch          50                                                        lactose             190                                                       magnesium stearate  6                                                         ______________________________________                                    

The above ingredients are mixed intimately and pressed into singlescored tablets.

EXAMPLE 35

    ______________________________________                                        Ingredients       Quantity per capsule, mgs.                                  ______________________________________                                        5-(N-methyl-2-pyrroyl)-1,2-                                                   dihydro-3H-pyrrolo- 1,2-a!-                                                   pyrrole-1-carboxylic acid                                                                       100                                                         lactose           148                                                         dextrose          2                                                           ______________________________________                                    

The above ingredients are mixed and introduced into a hard-shell gelatincapsule.

50 Mg. of (l)- 5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo-1,2-a!pyrrole-1-carboxylic acid is substituted for the 100 mg. of the(dl) compound of the above composition.

EXAMPLE 36

    ______________________________________                                        Ingredients        Quantity per capsule, mgs.                                 ______________________________________                                        methyl 5-(N-methyl-2-pyrroyl)-                                                1,2-dihydro-3H-pyrrolo- 1,2-a!-                                               pyrrole-1-carboxylate                                                                            158                                                        lactose            92                                                         ______________________________________                                    

The above ingredients are mixed and introduced into a hard-shell gelatincapsule.

EXAMPLE 37

    ______________________________________                                        Ingredients         Quantity per tablet, mgs.                                 ______________________________________                                        isoamyl 5-(N-methyl-2-pyrroyl)-                                               1,2-dihydro-3H-pyrrolo- 1,2-a!-                                               pyrrole-1-carboxylate                                                                             127                                                       lactose             91                                                        cornstarch          25                                                        magnesium stearate  2                                                         gelatin             5                                                         ______________________________________                                    

The above ingredients are mixed and pressed into single tablets.

EXAMPLE 38

    ______________________________________                                        Ingredients         Quantity per tablet, mgs.                                 ______________________________________                                        calcium 5-(N-methyl-2-pyrroyl)-                                               1,2-dihydro-3H-pyrrolo 1,2-a!-                                                pyrrole-1-carboxylate                                                                             230                                                       cornstarch (paste)  40                                                        cornstarch          50                                                        magnesium stearate  2                                                         lactose             178                                                       ______________________________________                                    

The above ingredients are thoroughly mixed and pressed into singlescored tablets.

EXAMPLE 39

    ______________________________________                                        Ingredients        Quantity per tablet, mgs.                                  ______________________________________                                        sodium 5-(N-methyl-2-pyrroyl)-                                                1,2-dihydro-3H-pyrrolo- 1,2-a!-                                               pyrrole-1-carboxylate                                                                            217                                                        cornstarch         50                                                         magnesium stearate 2                                                          gelatin            226                                                        lactose            5                                                          ______________________________________                                    

The above ingredients are mixed intimately and pressed into singlescored tablets.

EXAMPLE 40

    ______________________________________                                        Ingredients       Quantity per capsule, mgs.                                  ______________________________________                                        isopropylammonium 5-(N-                                                       methyl-2-pyrroyl)-1,2-                                                        dihydro-3H-pyrrolo- 1,2-a!-                                                   pyrrole-1-carboxylate                                                                           122                                                         cornstarch        30                                                          lactose           98                                                          ______________________________________                                    

The above ingredients are mixed and introduced into a hard-shell gelatincapsule.

EXAMPLE 41

    ______________________________________                                        Ingredients      Quantity per capsule, mgs.                                   ______________________________________                                        isoamyl 5-(N-methyl-2-                                                        pyrroyl)-1,2-dihydro-3H-                                                      pyrrolo- 1,2-a!pyrrole-1-                                                     carboxylate      32                                                           lactose          101                                                          cornstarch       15                                                           magnesium stearate                                                                             2                                                            ______________________________________                                    

The above ingredients are mixed and introduced into a hard-shell gelatincapsule.

EXAMPLE 42

An injectable preparation buffered to a pH of 7 is prepared having thefollowing composition:

    ______________________________________                                        5-(N-methyl-2-pyrroyl)-1,2-                                                   dihydro-3H-pyrrolo- 1,2-a!-                                                   pyrrole-1-carboxylic acid                                                                          0.2 g                                                    K.sub.2 HPO.sub.4 buffer (0.4 M                                               solution)            2 ml.                                                    KOH (1N)             q.s. to pH7                                              water (distilled sterile)                                                                          q.s. to 20 ml.                                           ______________________________________                                    

0.1 G. of (l)- 5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo-1,2-a!pyrrole-1-carboxylic acid is substituted for the 0.2 g. of the(dl) compound of the above composition.

EXAMPLE 43

A suppository totaling 2.8 grams is prepared having the followingcomposition:

    ______________________________________                                        5-(N-2-methyl-2-pyrroyl)-                                                     1,2-dihydro-3H-pyrrolo-                                                        1,2-a!pyrrole-1-car-                                                         boxylic acid         25 mg.                                                   Witepsol H-15                                                                 (triglycerides of satu-                                                       rated vegetable fatty                                                         acids; a product of                                                           Riches-Nelson, Inc.,                                                          New York, N.Y.)      balance                                                  ______________________________________                                    

12.5 Mg. of (l)- 5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo-1,2-a!pyrrole-1-carboxylic acid is substituted for the 25 mg. of the(dl) compound of the above composition.

EXAMPLE 44

An oral suspension for pediatric use is prepared having the followingcomposition:

    ______________________________________                                        5-(N-methyl-2-pyrroyl)-1,2-                                                   dihydro-3H-pyrrolo- 1,2-a!-                                                   pyrrole-1-carboxylic acid                                                                          0.1 g.                                                   fumaric acid         0.5 g.                                                   sodium chloride      2.0 g.                                                   methyl paraben       0.1 g.                                                   granulated sugar     25.5 g.                                                  sorbitol (70% solution)                                                                            12.85 g.                                                 Veegum K (Vanderbilt Co.)                                                                          1.0 g.                                                   flavoring            0.035 ml.                                                colorings            0.5 mg.                                                  distilled water      q.s. to 100 ml.                                          ______________________________________                                    

0.05 G of (l)- 5-benzoyl-1,2-dihydro-3H-pyrrolo-1,2-a!pyrrole-1-carboxylic acid is substituted for the 0.1 g. of the(dl) compound of the above composition.

EXAMPLES 45-46

Powdered top dressings for veterinary use are prepared having thefollowing compositions:

    ______________________________________                                                        Ex. 45   Ex. 46                                               ______________________________________                                        5-(N-methyl-2-pyrroyl)-                                                       1,2-dihydro-3H-pyrrolo-                                                        1,2-a!pyrrole-1-car-                                                         boxylic acid      0.1 g.     1.2 g.                                           sucrose           5.7 g.     3.7 g.                                           polyvinyl pyrrolidone                                                                           0.3 g.     0.3 g.                                           ______________________________________                                    

0.05 G. of (l)- 5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo-1,2-a!pyrrole-1-carboxylic acid is substituted for the 0.1 g. of the(dl) compound of the composition of Example 45.

0.6 G. of (l)- 5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo-1,2-a!pyrrole-1-carboxylic acid is substituted for the 1.2 g. of the(dl) compound of the composition of Example 46.

What is claimed is:
 1. A compound selected from the group of thoserepresented by the formula ##STR8## and the individual (l)-acid and(d)-acid isomers thereof and the pharmaceutically acceptable, non-toxicalkyl esters having from one to twelve carbon atoms and salts thereof,wherein each of R and R¹ is independently hydrogen or a lower alkylgroup having from 1 to 4 carbon atoms.
 2. A compound of claim 1 whereinR is hydrogen.
 3. A compound of claim 1 wherein R is methyl.
 4. Thecarboxylic acid compound of claim 2 wherein R¹ is hydrogen,5-(2-pyrroyl)-1,2-dihydro-3H-pyrrolo 1,2-a! pyrrole-1-carboxylic acid.5. The isopropyl ester of the compound of claim 4, isopropyl5-(2-pyrroyl)-1,2-dihydro-3H-pyrrolo 1,2-a!pyrrole-1-carboxylate.
 6. Thecarboxylic acid compound of claim 2 wherein R¹ is methyl,5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo 1,2-a!pyrrole-1-carboxylicacid.
 7. The isopropyl ester of the compound of claim 6, isopropyl5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo1,2-a!pyrrole-1-carboxylate acid.
 8. The carboxylic acid compound ofclaim 3 wherein R¹ is hydrogen,5-(2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo 1,2-a!pyrrole-1-carboxylicacid.
 9. The isopropyl ester of the compound of claim 8, isopropyl5-(2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo1,2-a!pyrrole-1-carboxylate.
 10. The carboxylic acid compound of claim 3wherein R¹ is methyl,5-(N-methyl-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo1,2-a!pyrrole-1-carboxylic acid.
 11. The isopropyl ester of the compoundof claim 10, isopropyl5-(N-methyl-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo1,2-a!pyrrole-1-carboxylate.
 12. A sodium, potassium or calcium salt ofthe compounds according to Formula (A) of claim
 1. 13. The sodium saltcompound of claim 12 wherein R is hydrogen and R¹ is methyl, sodium5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo1,2-a!pyrrole-1-carboxylate.
 14. An (l)-acid isomer of Formula (A) ofclaim
 1. 15. The compound of claim 14 wherein R is hydrogen and R¹ ismethyl, (l)-5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrroyl1,2-a!pyrrole-1-carboxylic acid.
 16. A sodium, potassium or calcium saltof an (l)-acid isomer of Formula (A) of claim
 1. 17. The sodium saltcompound of claim 16 wherein R is hydrogen and R¹ is methyl, sodium(l)-5-(N-methyl-2-pyrroyl)-1,2-dihydro-3H-pyrrolo1,2-a!pyrrole-1-carboxylate.
 18. A composition for treatinginflammation, pain or pyrexia in mammals consisting essentially of apharmaceutically acceptable non-toxic excipient and a therapeuticallyeffective amount of a compound represented by the formula ##STR9## orthe (l)-acid isomers of Formula (A), and the pharmaceuticallyacceptable, non-toxic alkyl esters having from one to twelve carbonatoms and salts thereof, wherein each of R and R¹ is independentlyhydrogen or a lower alkyl group having from 1 to 4 carbon atoms.
 19. Amethod of treating inflammation, pain or pyrexia in mammals whichcomprises administering to a mammal suffering therefrom atherapeutically effective amount of a compound represented by theformula ##STR10## or the (l)-acid isomer of Formula (A), and thepharmaceutically acceptable, non-toxic alkyl esters having from one totwelve carbon atoms and salts thereof, wherein each of R and R¹ isindependently hydrogen or a lower alkyl group having from 1 to 4 carbonatoms.
 20. A composition for administration to a pregnant mammal todelay onset of parturition consisting essentially of a pharmaceuticallyacceptable non-toxic excipient and a thereapeutically effective amountof a compound represented by the formula ##STR11## or the (l)-acidisomers of Formula (A), and the pharmaceutically acceptable, non-toxicalkyl esters having from one to twelve carbon atoms and salts thereof,wherein each of R and R¹ is independently hydrogen or a lower alkylgroup having from 1 to 4 carbon atoms.
 21. A method comprisingadministering to a pregnant mammal to delay the onset of parturition apharmaceutically effective amount of a compound selected from the groupof compounds represented by the formula ##STR12## or the (l)-acidisomers of Formula (A), and the pharmaceutically acceptable, non-toxicalkyl esters having from one to twelve carbon atoms and salts thereof,wherein each of R and R¹ is independently hydrogen or a lower alkylgroup having from 1 to 4 carbon atoms.
 22. The method of claim 21wherein said pregnant mammal is a woman who is not suffering frominflammation, pyrexia, or pain.
 23. The method of claim 22 wherein saidpregnant woman has had a previous spontaneous abortion, miscarriage orpremature delivery, which occurred prior to the time for normalparturition at or about full term.
 24. The method of claim 21 whereinsaid pregnant mammal is a woman who is not suffering from inflammation,pyrexia or nonparturition-causing pain but who is experiencing uterinemuscle contractions, said compound being administered in atherapeutically effective amount adapted to reduce the intensity orduration of the uterine muscle contractions, stop the uterine musclecontractions altogether, whereby termination of the pregnancy ispostponed from the time it otherwise would have happened.